ES2380653T3 - Beta-cyclodextrin-drospirenone inclusion complexes - Google Patents

Abstract

An inclusion complex between ß-cyclodextrin and drospirenone, where the inclusion complex between drospirenone and ß-cyclodextrin is in a 1: 3 molar ratio.

Description

Β-Cyclodextrin-Drospirenone Inclusion Complexes

5 FIELD OF THE INVENTION

The present invention relates to an inclusion complex formed between β-cyclodextrin and drospirenone, and methods for providing such an inclusion complex. In addition to this, the present invention relates to the use of said inclusion complex in pharmaceutical compositions for use as a medicament in the

10 treatment of symptoms associated with menopause and female contraception.

BACKGROUND OF THE INVENTION

Drospirenone (6β, 7β; 15β, 16β-dimethylene-3-oxo-17α-4-eno-21,17-carbolactone), which can be prepared

15 substantially as described, e.g. For example, in US 4,129,564 or WO 98/06738, it is only sparingly soluble in aqueous media at various pH values.

The water solubility of a compound is extremely relevant with respect to its usefulness in the industry, particularly in the pharmaceutical industry, where there is a strong link between water solubility and

20 bioavailability. The therapeutic efficacy of drospirenone can be improved by increasing its overall solubility in water, thus providing alternative routes of administration to those that continue through the gastrointestinal tract, where absorption is slow and is then rapidly expelled from the circulating blood by the liver. .

It is known that cyclodextrins solubilize non-polar compounds and improve the absorption of certain compounds by complexing with said compounds. Cyclodextrins are frequently derivatized in order to improve solubility or to properly accommodate the compound of interest. However, certain compounds are not well housed by the cavity of some of the cyclodextrin molecules.

Drospirenone, in its uncomplexed form, is known from DE 26 52 761, which describes its use as a diuretic compound.

EP 0 398 460 describes the use of drospirenone for contraception and for symptoms associated with menopause.

US 4,596,795 describes a complex between α-, β- and γ-cyclodextrins and derivatives thereof with testosterone, progesterone and estradiol, and the solubility of said complexes.

US 5,885,978 refers to a composition comprising an adrenocortical steroid and cyclodextrin prepared by caging the adrenocortical steroid into the cyclodextrin using a homomixer.

US 5,376,641 describes a method for producing a water soluble steroid by mixing a steroid and a branched beta-cyclodextrin together in water for a period of 4 to 24 hours under ambient conditions.

US 5,376,641 describes a method of producing a water soluble steroid by complexing the steroid with branched β-cyclodextrin.

US 4,727,064 describes a method for improving the dissolution properties of a steroid

50 forming a solid comprising at least one of testosterone, progesterone and estradiol as an inclusion complex with a poly-β-cyclodextrin and / or hydroxypropyl-β-cyclodextrin intended for oral administration.

FR 2 515 187 describes inclusion complexes between γ-cyclodextrins and various steroids such as the steroid spironolactone.

WO 96/02277 describes pharmaceutical compositions containing cyclodextrinaclatrato complexes of steroid sex hormones for protection against oxidative degradation of steroids.

SUMMARY OF THE INVENTION

The invention relates to an inclusion complex between β-cyclodextrin and 6β, 7β; 15β, 16β-dimethylene-3-oxo-17αpregn-4-eno-21,17-carbolactone (drospirenone), in which the molar ratio between drospirenone and the β-cyclodextrin is

1: 3

The invention also relates to a method of producing the inclusion complex according to the invention.

An object of the present invention is to increase the water solubility of drospirenone. The present invention thus further describes methods for improving the solubility of drospirenone, said method comprising forming an inclusion complex between drospirenone and β-cyclodextrin.

In a further aspect of the invention, pharmaceutical compositions comprising an inclusion complex of drospirenone and β-cyclodextrin are described. Therefore, this specification defines the inclusion complex between drospirenone and β-cyclodextrin for use for female contraception or for the treatment of menopausal symptoms.

DETAILED DESCRIPTION OF THE INVENTION

The term "inclusion complex" is intended to mean a complex where at least one drospirenone residue has been inserted by itself, at least partially, into the cyclodextrin cavity.

In efforts to improve the functional utility of drospirenone, research has led to a new chemical entity, an inclusion complex between β-cyclodextrin and drospirenone in a 3: 1 molar ratio.

The β-cyclodextrin can be modified so that some or all of the primary or secondary hydroxyls of the macrocycle, or both, can be rented or acylated. Methods for modifying these alcohols are well known to the person skilled in the art, and many derivatives are commercially available. Β-Cyclodextrin can be modified so that one or more of the primary or secondary hydroxyl of the macrocycle, or both, can be rented or acylated. Methods for modifying these alcohols are well known to the person skilled in the art, and many are commercially available. Thus, some or all of the β-cyclodextrin hydroxyls may have been substituted with an OR group or an OC (O) -R group, wherein R is an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl , an optionally substituted C2-6 alkynyl, an optionally substituted aryl or heteroaryl group. R may be a methyl, ethyl, propyl, butyl, pentyl or hexyl group. Therefore, O-C (O) -R may be an acetate. In addition, R may be such that β-cyclodextrin derivatize with the 2-hydroxyethyl group, or the 2-hydroxypropyl group, commonly employed. In addition, β-cyclodextrin alcohols can be per-benzyl, per-benzoylated, or benzyl or benzoylated on only one side of the macrocycle, or where only 1, 2, 3, 4, 5 or 6 hydroxyls are benzylated or benzoylated The β-cyclodextrin hydroxyl groups can be per-alkylated or per-acylated such as per-methylated or per-acetylated, or alkylated or acylated, such as methylated or acetylated on only one side of the macrocycle, or where only 1, 2, 3 , 4, 5 or 6 hydroxyls are alkylated or acylated such as methylated or acetylated.

Without being limited to a particular way in which the inclusion complex is formed, it is presumed that the inclusion complex is an inclusion complex where hydrophobic interactions favor the inclusion of hydrophobic moieties from drospirenone in the cavity of a β molecule. -cyclodextrin, given the relative hydrophobicity of the numerous alkyl groups in the β-cyclodextrin cavity.

The term "solubility" in relation to drospirenone is intended to mean the solubility of the inclusion complex between drospirenone and β-cyclodextrin in water. The term "total solubility" refers to the concentration of drospirenone in a phase solubility isotherm, namely the solubility of uncomplexed and complexed drospirenone. "Total solubility" is a function of the concentration of β-cyclodextrin.

Since one of the objects of the present invention is to increase the solubility and total solubility of drospirenone, it is preferred that the inclusion complex be such that the total water solubility of drospirenone at 20 ° C is increased by a factor of at least 2 , such as at least 2.5, at least 3, at least 3.5 or at least 4 compared to drospirenone in an uncomplexed form.

Correspondingly, it is preferred that the total solubility of drospirenone in water at 20 ° C be increased by at least 9 x 10-5 mol / L, such as at least 1 x 10-4 mol / L, 2 x 10-4 mol / L, 3 x 10-4 mol / L or 3.5 x 10-4 mol / L.

The inclusion complex may exist in the form of a hydrate containing varying amounts of water such as between about 1% and 25% water. The degree of hydration may vary according to, among other reasons, the degree of hydroxyl substitution and the method of preparation. The water content of the inclusion complex may depend on the manner in which the inclusion complex is stored, temperature, pressure and relative humidity. Thus, any discussion about the solid state form of the drospirenone-cyclodextrin inclusion complex comprises the hydrate range. The hydrate water is part of the crystalline framework and, thus, by modifying the water content, the crystalline framework can be changed and possibly some of the physical properties of the inclusion complex.

As is known to the person skilled in the art, β-cyclodextrin itself forms an inclusion complex with water. Thus, the β-cyclodextrin used in the preparation of the drospirenone-βcyclodextrin inclusion complex may be in a hydrated form or in an anhydrous form.

A further object of the invention is to provide a method for producing an inclusion complex, comprising the step of combining β-cyclodextrin and drospirenone at a molar ratio of 0.3: 1 to 20: 1, preferably 1: 1, 2 : 1, 3: 1, 4: 1 or 5: 1, most preferably 2: 1 or 3: 1, particularly 3: 1.

The term "solution" in relation to β-cyclodextrin or drospirenone and in relation to the preparation of an inclusion complex is intended to comprise embodiments where the solute, namely β-cyclodextrin or drospirenone, is totally or partially dissolved in the solvent with the in order to form a homogeneous solution, a saturated solution, a super-saturated solution, a thick aqueous suspension or a suspension.

In the preparation of the inclusion complex according to the present invention, the combination of the components can be performed using a β-cyclodextrin solution comprising organic solvent or an aqueous solution such as water. In sensitive embodiments of the invention, the solvent comprises a mixture of water and an organic solvent. The organic solvent may be selected from any of those commonly used in organic syntheses such as, but not limited to THF, methylene chloride, diethyl ether, petroleum ether, ethyl acetate, dioxane, DMF, DMSO, acetone, acetonitrile, ethanol, methanol, pyridine or combinations thereof. Preferably, the organic solvent is miscible with water. Polar solvents such as water, methanol, ethanol, DMSO, DMF and pyridine, most preferably water or ethanol, particularly water, are preferred.

A solution of β-cyclodextrin, as described above, at any concentration or degree of homogeneity, can be combined with solid drospirenone. Alternatively, the β-cyclodextrin solution can be combined with a drospirenone solution. In the embodiment in which a solution of β-cyclodextrin is combined with solid drospirenone, drospirenone may be in its micronized form.

In the embodiment in which a solution of β-cyclodextrin is combined with a solution of drospirenone, drospirenone may be totally or partially dissolved in an organic solvent or water. Organic solvents may be selected from any of those known to the person skilled in the art such as, but not limited to THF; methylene chloride; diethyl ether, petroleum ether, ethyl acetate, dioxane, DMF, DMSO, acetone, acetonitrile, ethanol, methanol, pyridine or combinations thereof.

It follows that a solution of drospirenone, as described above, in any degree of homogeneity and in any concentration can be combined with solid β-cyclodextrin in the preparation of an inclusion complex between β-cyclodextrin and drospirenone.

Alternatively, solid drospirenone and solid β-cyclodextrin can be combined in their solid forms and then combined with water or an organic solvent.

In a preferred embodiment of the invention, a method for producing an inclusion complex comprises the steps of dissolving β-cyclodextrin in water, optionally with heating aid, to form a β-cyclodextrin solution; dissolving drospirenone in a solvent selected from the group comprising water and ethanol or mixtures thereof, optionally with heating aid, to form a drospirenone solution; combining the β-cyclodextrin solution and the drospirenone solution to form a combined solution; stir the combined solution, preferably while maintaining the solution at or below 25 ° C; filter the resulting precipitate; washing the precipitate with a solvent selected from the group consisting of water, ethanol, ether and acetone, preferably, wherein the solvent is cooled to below 25 ° C; optionally, suspend the resulting solid in a solvent, preferably acetone, and wash the suspended material with a solvent selected from the group consisting of water, ethanol, ether and acetone, preferably wherein the solvent is cooled to below 25 ° C; substantially separate the entire solvent from the solid material. Preferably, the solvent is removed by spray drying or, alternatively, by lyophilization.

The method of preparation may further comprise mechanical mixing, stirring or shaking, or heating of the combined solutions or components.

In embodiments of the invention in which an organic solvent is used in the combination of drospirenone or β-cyclodextrin, the inclusion complex formed may contain one or more molecules of said solvents, depending on the method of drying, precipitation or crystallization. Alternatively, the complex may exist in the form of a hydrate containing varying amounts of water.

A typical preparation of the drospirenone-β-cyclodextrin inclusion complex can be as follows: drospirenone is dissolved in a solvent such as acetone or ethanol. Β-Cyclodextrin dissolves in water at a temperature between 20 and 100 ° C, such as between 30 and 90 ° C, such as between 40 and 80 ° C, preferably between 40 and 60 ° C, such as at or near 40 ° C, 45 ° C, 50 ° C, 55 ° C or 60 ° C The drospirenone solution is added to the β-cyclodextrin solution, and the suspension obtained is stirred at 20-30 ° C for a few hours, such as about 0.5 to 48 hours, then stirred at 2 ° C for a few hours. The crystallized product is isolated and dried. In an alternative procedure, the drospirenone solution is added to the β-cyclodextrin solution, and the suspension obtained is stirred at temperatures below 25 ° C.

The inclusion complex can be prepared by methods described in or similar to those described in Examples 2 and 3.

The crystallized product can be washed with water, acetone and / or any other solvent in order to wash off the uncomplexed material. The solvent used to wash the crystallized product can be precooled to below 25 ° C. The crystallized product can be dried over a drying agent such as P2O5 or any other known by the person skilled in the art in a desiccator or vacuum cabinet for several hours or days. It can also be cooled in the desiccator during drying, or be subjected to spray drying or lyophilization.

A further object of the invention is to provide a pharmaceutical composition comprising a drospirenone and cyclodextrin inclusion complex as described above, together with one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition can be adapted to be administered orally, parenterally, through the mucosa or topically, vaginally, subcutaneously or nasally. The composition may comprise 0.1 mg to 10 mg of drospirenone, depending on its therapeutic application.

The inclusion complex of drospirenone and β-cyclodextrin can be used as a medicine. The inclusion complex of drospirenone and β-cyclodextrin can be used for the preparation of a pharmaceutical composition for female contraception or for the treatment of menopausal symptoms.

In suitable embodiments of the present invention, a pharmaceutical composition may comprise an inclusion complex between drospirenone and β-cyclodextrin and may further comprise one or more substances.

therapeutically active. The therapeutically active substance is preferably a steroid. The therapeutically active substance can be complexed with cyclodextrin. The pharmaceutical composition may comprise an inclusion complex of drospirenone and β-cyclodextrin, a therapeutically active substance such as estrogen

or progestogen or a gestagen together with one or more pharmaceutically acceptable carriers or excipients. 5

BRIEF DESCRIPTION OF THE EXAMPLES

Example 1 compares the solubility of drospirenone in water with the solubility of a sample of an inclusion complex consisting essentially of a 1: 1 molar ratio between β-cyclodextrin and drospirenone and with a

10 shows that it consists essentially of a 2: 1 molar ratio between β-cyclodextrin and dropirenone. The example illustrates the increase in the solubility of drospirenone by complexation with β-cyclodextrin. The example further describes the stability of the 1: 1 complex.

Examples 2 and 3 describe two alternative methods for the preparation of a complex between drospirenone and β15 CD (β-cyclodextrin).

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 represents the structure of drospirenone, β-cyclodextrin. β-cyclodextrin is a macrocycle consisting of 20 units of sugar.

EXAMPLES

25 Example 1

Drospirenone Solubility

The following data were obtained with the phase solubility diagram (PSD) technique in 30 aqueous solutions at 20 ° C. The stability constants of the inclusion compound from β-CD and drospirenone are provided

1: 1 complex stability constant

K11 = 2.2 x 10-4 M-1

Drospirenone Solubility

SDP = 4.14 x 10-5 mol / L (1.51 x 10-2 g / L)

Solubility of the 1: 1 complex

S1: 1 = 3.88 x 10-4 mol / L (0.516 g / L)

Solubility of the 1: 2 complex

S1: 2 = 3.79 x 10-5 mol / L (0.1 g / L)

Example 2

Preparation of a complex between drospirenone and β-CD

24 mmol of the β-cyclodextrin are dissolved in 970 mL of water at 45 ° C and, over the course of 30 min, 8 mmol of drospirenone dissolved in 90 mL of ethanol are added dropwise. After washing with an additional 5 mL of ethanol, cooling to room temperature, stirring at room temperature for 22 h and stirring in an ice bath (4 ° C) for 3 h, the precipitate was filtered off with suction in a fried G4. Then, the resulting complex was washed twice with 100 mL of ice water each time and twice with 50 mL of acetone

45 ice cold. It is then dried in a desiccator over phosphorus pentoxide.

Example 3

Preparation of a complex between drospirenone and β-CD

50 15.5 g of β-CD are dissolved in 1000 mL of water, heating if necessary. 1,468 g of drospirenone are weighed in the aqueous cyclodextrin solution. The suspension is stirred at room temperature for 72 h. Then it is stirred at + 2 ° C for 3 h. The solid is filtered off with suction in a G4 frit and washed twice with 100 mL of water each time. The crystals are suspended twice in 50 mL of acetone and filtered off with suction each time. Then they wash with 100 mL of water. The wet crystals are dried under vacuum over phosphorus pentoxide.

Claims (10)

1.- An inclusion complex between β-cyclodextrin and drospirenone, where the inclusion complex between drospirenone and β-cyclodextrin is in a 1: 3 molar ratio. The inclusion complex according to claim 1, further comprising one or more therapeutically active substances. 3. A method for producing an inclusion complex as defined in claim 1, comprising combining β-cyclodextrin and drospirenone in a molar ratio of 0.3: 1 to 20: 1. 4. The method according to claim 3, comprising the combination of a solution of drospirenone with a solution of β-cyclodextrin. The method according to claim 3, comprising the combination of solid drospirenone with a solution of β-cyclodextrin. 6. The method according to claim 4 or 5, wherein the β-cyclodextrin solution comprises a solvent selected from the group consisting of water, ethanol, acetone, acetonitrile, methanol, DMSO, pyridine or combinations thereof. themselves, preferably water. 7. The method according to claim 4, wherein the drospirenone solution comprises a solvent selected from the group consisting of water, ethanol, acetone, acetonitrile, methanol, DMSO, pyridine or combinations thereof, preferably water or ethanol. The method according to claim 3, comprising the steps of: dissolving β-cyclodextrin in water, optionally with heating, to form a solution of βcyclodextrin; dissolving drospirenone in a solvent selected from the group consisting of water and ethanol or mixtures thereof, optionally with heating, to form a drospirenone solution; combining the β-cyclodextrin solution and the drospirenone solution to form a combined solution; stir the combined solution, preferably while maintaining the solution at or below 25 ° C; 35 filter the resulting precipitate; washing the precipitate with a solvent selected from the group consisting of water, ethanol, ether and acetone, preferably where the solvent is cooled to below 25 ° C; optionally, suspending the resulting solid in a solvent, preferably acetone, and washing the suspended material with a solvent selected from the group consisting of water, ethanol, ether and acetone, preferably wherein the solvent is cooled to below 25 ° C; substantially remove all of the solvent from the resulting or suspended material. 9. The method according to claim 8, wherein the solvent separation is carried out by spray drying. The method according to claim 8, wherein the separation of the solvent is by lyophilization. 11. The method according to any of claims 3-10, further comprising combining a therapeutically active substance to the combined solution, the drospirenone solution or the β50 cyclodextrin solution. 12. A pharmaceutical composition comprising an inclusion complex of drospirenone and β-cyclodextrin as defined in claim 1 or 2, together with one or more pharmaceutically acceptable carriers or excipients. 13. The pharmaceutical composition according to claim 12, intended to be administered by 8 oral, parenteral, mucosal or topical, vaginal, subcutaneous or nasal administration. 14. The pharmaceutical composition according to claim 12 or 13, wherein the amount of drospirenone is 0.1 mg to 10 mg. 15. The pharmaceutical composition according to any of claims 12-14, further comprising one or more therapeutically active substances. 16. An inclusion complex according to claim 1 or 2 for use for female contraception. 17. An inclusion complex according to claim 1 or 2, for use in the treatment of menopausal symptoms.